Pharmaceutical compositions containing a novel ester of ((methylamino)methyl)benzyl alcohol and methods of using same

ABSTRACT

1. A PHARMACEUTICAL COMPOSITION COMPRISING A PHARMACEUTICALLY EFFECTIVE AMOUNT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF 3,4-DIPIVALYL-A-(METHYLAMINO)METHYL)BENZYL ALCOHOL AND ITS TERAPEUTICALLY ACCEPTABLE ACID ADDITION SALTS, ADMIXED WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER.

United States Patent 3,839,584 PHARMACEUTICAL COMPOSITIONS CONTAIN- INGA NOVEL ESTER OF [(METHYLAMINO) METHYL]BENZYL ALCOHOL AND NETHODS OFUSING SAME Anwar Hussain and James E..Truelove, Lawrence, Kans.,assignors to Interx Research Corporation, Lawrence, Kans.

No Drawing. Original application Aug. 31, 1972, Ser. No. 285,235, nowPatent No. 3,809,714. Divided and this application Nov. 16, 1973, Ser.No. 416,605

Int. Cl. A61k 27/00 U.S. Cl. 424-311 6 Claims ABSTRACT OF THE DISCLOSUREA novel ester of the general formula:

and the pharmaceutically acceptable acid condition salts thereof. Thecompound of the formula is useful as an antiglaucoma and broncholyticagent.

CROSS-REFERENCE TO RELATED APPLICATIONS This Application is a divisionalapplication of our earlier co-pending application, Ser. No. 285,235,filed on Aug. 31, 1972, now U.S. Pat. 3,809,714.

BACKGROUND OF THE INVENTION The present invention relates to both anovel and useful therapeutic ester of benzyl alcohol and topharmaceutical compositions for using same. More particularly, theinvention pertains to a new compound represented by Formula 1 of thefollowing general formula:

CH (H) CHa 1 C 0 H3 I CH3 OH H .5 J;

CHa- 'C--O H-CHr-N I ll CH3 0 CH3 Formula 1 and its pharmaceuticallyacceptable, non-toxic acid addition salts. The compound and its saltsare useful as astiglaucoma and broncholytic agents, and they can beadministered per se or in pharmaceutical composition form when admixedwith a pharmaceutically acceptable carrier.

A pharmaceutical and medical need exists for a new and useful compoundindicated for the management of glaucoma, bronchial asthma and othersympathomimetic activities. This need exists because the compound 3,4-dihydroxy-u-[(methylamino)methyl]benzyl alcohol, generally known asepinephrine, and widely used for the treatment of these medicalconditions, possesses certain inherent disadvantages. For example, onedisadvantage associated with the prior art compound is its instabilityto both air and light and it is subject to chemical attack by manyagents that are conventionally used in pharmaceutical preparations. Pastattempts by the prior art to overcome these particular disadvantageshave not met with any acceptable success. One attempt involvedacidifying solutions containing the drug which solutions were irritatingto body tissue, and if these solutions later were adjusted to aphysiological pH, the free drug frequently precipitated anddeterioration followed. One attempt to protect the drug againstoxidative deterioration consists in adding the antioxidant sodiumbisulfite to a solution containing the drug. But, this anti-oxidantchemically attacked the aliphatic side chain of the drug to form abiologically inactive derivative thereof. Also, the prior art3,4-dihydroxy-a- (methylamino)methyl] benzyl alcohol had poor lipoidsolubility attributed to its hydrophilic phenolic hydroxyl groups whichtended to restrict the medical application of the drug. This common andwide use of 3,4-dihydroxy-a- (methylamino)methyl] benzyl alcohol withtheir accompanying disadvantages creates an immediate and pressing needfor a new and useful pharmaceutical compound that possesses therapeuticproperties useful for treating bronchial asthma, glaucoma and the likewhile remaining essentially free from the unwanted disadvantagesassociated with the prior art compounds.

SUMMARY OF THE INVENTION- Accordingly, it is an immediate object of thisinvention to provide a novel pharmaceutical compound and its acceptableacid addition salts that are useful as an antiglaucoma agent, fortreating bronchial asthma and as a syrnpathomimetic agent.

Another object of the invention is to provide a novel and usefulphysicochemical ester of 3,4-dihydroXy-u- [(methylamino)methyl1benzylalcohol and its acceptable salts that are essentially free from theunwanted elfects associated with the prior art.

Still another object of the invention is to provide a new and useful'3,4-dipivalyl-a-[(methylamino)methyl] benzyl alcohol that possessesincreased stability and solubility and can be administered in standard,pharmaceutical formulations.

Yet still another object of the invention is to provide the compound 3,4dipivalyl-tat-[(methylamino)methyl] benzyl alcohol as a usefultherapeutic agent that has improved lipoid solubility for enhancedresorption when administered to warm blooded animal tissue.

Yet still another object of the invention is to provide3,4-dipivalyl-a{(methylamino)metlhyl]benzyl alcohol that can beadministered per se or can be dispensed in ophthalmic, aerosol and othertypes of pharmaceutical formulations to warm blooded animals to producea local or systemic physiological or pharmacological beneficial effect.

Other objects, features and advantages of the invention will be apparentto those skilled in the art from the detailed description of theinvention which follows, taken in conjunction with the accompanyingclaims.

DETAILED DESCRIPTION OF INVENTIVE EMBODIMENTS In attaining the objects,features and advantages of the present invention, it has now been foundthat the compound embraced by Formula 1 H 0 Formula 1 and itspharmaceutically acceptable salts can be made available to the art for'use as an antiglaucoma agent, for use in the management of bronchialasthma, and for use as a general sympathomimetic agent that acts onpostganglionic adrenergic nerve ending structures innervated by them andpossessing and enhanced rate of absorption while simultaneouslyovercoming the problems associated with the prior art can be synthesizedby the now described procedures.

The novel 3,4-dipivalyl a [(methylamino)mcthyl]- benzyl alcohol ofFormula 1, which can also be conveniently named 1-(3,4dipivalylphenyl)-2-(methylamino) ethanol or 3,4-dipivalyl-l-[l-hydroxy 2(methylamino) ethyl]benzene is prepared by first contacting and reactingan whale-3,4-dihydroxyacetophenone with stoichiometric amounts, usuallywith an excess of a lower alkylamine; for example, with about 1 to about30 or more molecular equivalents of the alkylamine for each reactivehalogen moiety present in the a-halo-3,4-dihydroxyacetophenone presentas a reactant. The reaction is carried out in the presence of a suitablesolvent, at a temperature of about 10 C. to about 75 C., usually atambient temperature of about 25 C., and at atmospheric pressure, orhigher pressures of from 1 to about 10 atmospheres and the like. Thestanding reactants begin to react on contact, but it is generallypreferable to carry out the reaction for about 10 minutes to about 48hours to produce from the starting materials the corresponding product,u-lower alkylamino-3,4-dihydroxyacetophenone.

Next, the hydroxyl groups of the product (Mower-3,4-dihydroxyacetophenone at positions C-3 and C-4 of the aryl ring areesterified by reacting an acylating agent with the hydroxyl group in anorganic medium. Examples of acylating agents suitable for esterifyingthe hydroxyl groups include anhydrides, mixed anhydrides, the chlorideof the appropriate alkanoic acid, and the like. The acylation is carriedout by contacting and reacting the hydroxyl groups with, for example, anacid chloride pivalyl chloride, in the presence of a solvent, at atemperature of 5 C. to 100 C., usually at refluxing temperature, and ata pressure of 1 atmosphere or higher, for about 2 hours to 24 hours orlonger. Generally, the reactants are present in equivalent amounts, orin excess thereof, for example, 1 to moles of acid chloride to 1 mole ofhydroxyl reactant. The acylated product is recovered by precipitatingwith an organic solvent, followed by conventional organic extraction andreprecipitation with an aqueous media to yield the product, (X-lOWCfalkylamino-3,4-dipivalyl acetophenone.

The aliphatic side chain keto functionality is conveniently reduced tothe corresponding alcohol group very smoothly and in good yield by thecatalytic hydrogenation of the 0t-10\VCF alkylamino-3,4-dipivalylacetophenone. Generally, the hydrogenation is carried out in thepresence of a nobel metal catalyst such as platinum, palladium, rhodium,platinium oxide and the like. The reduction of the ketone in a hydrogenenvironment, usually atmospheres to 180 atmospheres and the like, and atroom temperatures, or with heating from about 20 C. to 75 C. or thelike. The catalytic hydrogenation is usually carried out in a standardParr vessel, or the like. The carbonyl can also be reduced by standardmethods such as metal hydride reduction, and the like. Modern SyntheticReactions, by House, H. 0., pp. 1 to 22, 1965, published by W. A.Benjamin, Inc., New York.

The resolution of the racemate can be carried out by conventionalstandard resolution methods well known to those in the art as describedin Organic Chemistry, by Fieser and Fieser, pp. 270 to 281, 1944,published by DC. Heath and Company, Boston; and, Organic Chemistry, byMorrison and Boyd, pp. 231 to 233, 1969, published by Allyn and Bacon,Inc., Boston.

The phrases, pharmaceutically acceptable and nontoxic, acid additionsalts as used herein generally includes the non-toxic acid additionsalts of the compounds of Formula 1, formed with non-toxic inorganic ororganic acids. For example, the salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycollic, stearic, lactic,malic, tartaric, citric, ascorbic, parnoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, fumaric,salicylic, toluenesulfonic, and the like.

The pharmaceutically acceptable acid addition salts of the presentinvention can be synthesized from the compound embraced by Formula 1 byconventional, chemical methods. Generally, the salts are prepared byreacting the free base with stoichiometric amounts or with an excessthereof of the desired salt forming inorganic or organic acid in asuitable solvent or various combination of solvents. For example, thefree base can be dissolved in a mixed aqueous solution of theappropriate acid and the salt recovered by standard techniques, forexample, by evaporation of the solution. Alternatively, the free basecan be charged into an organic solvent such as a lower alkanol, asymmetrical or unsymmetrical ether containing 2 to 10 carbon atoms, analkyl ester, or mixtures thereof, and the like, and then it is treatedwith the appropriate acid to form the corresponding salt. The salt isrecovered by standard, recovery techniques, for example, by filtrationof the desired salt on spontaneous separation from the solution, or itcan be precipitated by the addition of a solvent in which the salt isinsoluble and recovered therefrom.

Examples of suitable inorganic and organic solvents for performing thevarious reactions include any inorganic or organic solvent that does notadversely effect the reactants or the resulting product includinghalogenated solvents such as methylene chloride, chloroform, carbontetrachloride, ethylene chloride, ether solvents such as diethyl ether,dimethyl ether, and other solvents such as tetrahydrofuran, dioxane,diglyme, n-hexane, cyclooctane, benzene, heptanc, cyclohexane; mixturesthereof, and like aliphatic, cycloaliphatic and aromatic hydrocarbonsolvents, water, acidified aqueous solutions, mixed organic andinorganic solutions, ethyl acetate, propyl acetate, and the like.

The following examples are set forth as representative methodsillustrative of the spirit of the present invention. These examples arenot to be construed as limiting the scope of the invention as otherfunctionally equivalent means Will be readily apparent to those skilledin the subject art in the light of the present specification and theaccompanying claims.

EXAMPLE 1 Synthesis of 3,4-dipavalyl-a-[(methylamino)methyl]- benzylalcohol. First, 0.27 moles of a-chloro-3',4-dihydroxyacetophenone,Formula 2, are dissolved in 200 ml. methanol with warming. Next, onehundred ml. of a 40% aqueous solution of methylamine is slowly added andthe mixture stirred at 50-55 C. for two hours. The reaction mixture isthen stirred an additional 24 hours at room temperature.

The crude product separates as a solid from the reaction medium and isrecovered by filtration, and it is then washed thoroughly with ether anddissolved in 350 ml. 1N HCl. Then, approximately 250 ml. of the aqueoussolvent is removed with a rotary evaporator and the evaporation residuecombined with ml. methanol and filtered through decolorizing charcoal.The product, Formula 3, is precipitated as the HCl salt by the additionof seven parts of acetone. The resulting crystalline material is removedby filtration dried at 40 C. with vacuum, and has a melting point ofabout 242 C. and is used without further purification.

Next, 25.3 grams, 0.125 mole, of compound 3 are dissolved in 250 ml.ethyl acetate and 0.125 moles perchloric acid as a 70% aqueous solutionis slowly added thereto with continuous stirring. Then, an excess ofpivalyl chloride, Formula 4, 280 ml., is added and the mixture slowlywarmed to reflux temperature. The reaction mixture is refluxed for aboutfive hours and allowed to cool to room temperature with continuousstirring. The product is precipitated as the perchlorate salt by theaddition of perchloric acid, H010 in 500 ml. ether. The product, Formula5, is isolated and purified by dissolving in 75 ml. acetone andprecipitating it with 150 to 200 ml. of water.

To 20 grams of compound of Formula 5 dissolved in 300 ml. 95% ethanol ina Parr reaction vessel is added 1.5 grams Adams catalyst, platinumdioxide, and the mixture shaken under hydrogen at 50 p.s.i. for one hourat ambient temperature. The mixture is then filtered and the ethanolremoved on a standard rotary evaporator. The resulting oil is dissolvedin 200 ml. ether and slowly added to 1200 ml. ether with continuousstirring. The product, Formula 6, separates as crystals which areremoved after 15-30 minutes by filtration. The compound melts at 146-147C. and needs no further purification.

The racemate, Formula 6, is resolved by fractional crystallization ofthe dibenzoyl-d-bitartrate salt as follows: first, 8.4- grams of sodiumdibenzoyl-d-bitartrate. Formula 7, are dissolved in 200 ml. methanol andthe solution filtered. Next, 20 grams of compound 6 are dissolved in 200ml. methanol, filtered and diluted with 400 ml. water. The solution ofthe sodium dibenzoyl-d-bitartrate is added to the aqueous methanolsolution of 5 and the total volume adjusted to 840 ml. with a 1 to 1mixture of methanol and water. This solution is seeded with knowndibenzoyl-bitartrate salt of l-dipivalylepinephrine, Formula 8, andcooled at a rate of 0.8 degrees per hour until the final temperature is2.6 C. The product, Formula 8, is removed by filtration andrecrystallized from 1 to l methanol/ water by the procedure above. Theproduct has a melting point of 149-150 C. and a specific rotation ofabout -25. This sequence is outlined below:

i H COH2C1 CH8NH2 Formula 2 HO- C-CHzNHCHa-HCI Formula 3 H0104(CHa)3C-C-CL Formula 4 0 ll: 0 a)sC 0 H CHzNHCHs-HCIOA Hq/Pt 0 u(CHa)3CCO Formula 5 0 ll (CH1)3C- O (|)H (|JCH1NHCH O G H n (CH3)30 COFormula 6 0 0 Na t f HO--0("J OOH 0 Formula 7 (CHahC--J) O 6 s-omwmon,

Formula 8 EXAMPLE 2 OH O 01% CH; Cl HO Formula 9 Formula 10 0 (u,NHflCHi Repeat HO- CHaCL Example 1 Formula 11 Formula 12 The novelcompound and its pharmaceutically acceptable salts can be used by thepharmaceutical and the veterinary arts for their antiglaucoma, treatingbronchial asthma including hay fever and allergic rhinitis in a varietyof pharmaceutical preparations or veterinary preparations. In thesepreparations, the new compound and its non-toxic salts are administrablein the form of injectables, solutions, suppositories, ointment,emulsions, jellies, buccal patches, oral inhalant, nasal inhalant,aerosol, and in other suitable forms. The pharmaceutical or veterinarypreparation which contains the compound is conveniently admixed with anon-toxic pharmaceutical organic carrier, or with a non-toxicpharmaceutical inorganic carrier, usually from 0.1 micrograms to 10grams, and the like. Typical of pharmaceutically acceptable carriersare, for example, water, mixtures of water and watermiscible solventssuch as lower alkanols or aral kanols, vegetable oils, polyalkyleneglycols, petroleum based jelly, ethyl celluose, ethyl oleate,carboxymethylcellulose, polyvinylpyrrolidone, isopropyl rnyristate andother conventionally employed acceptable carriers. The pharmaceuticalpreparation may also contain non-toxic auxiliary substances such asemulsifying, preserving, wetting agents, bodying agents and the like, asfor example, polyethylene glycols 200, 300, 400 and 600, carbowaxes1,000, 1,500, 4,000 and 10,000, bacterial components such as quaternaryammonium compounds, phenylmercuric salts known to have cold sterilizingproperties and which are non-injurious in use, thimerosal, propylparaben, buffering ingredients such as sodium chloride, sodium borate,sodium acetate, gluconate buffers, and other conventional ingredientssuch as sorbitan monolaurate, triethanolamine oleate, polyoxyethylenesorbitan monopalmitylate, dioctyl sodium sulfosuccinate,monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and thelike. Additionally, suitable ophthalmic vehicles can be used as carriermedia for the present purpose including conventional phosphate buttervehicle systems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles, and the like.

Exemplary of a typical method for preparing an ophthalmic compositioncontaining L 3,4 dipivalyla [(methylamino)methyl]benzyl alcohol salt,sodium chloride, chlorobutanol, oxime sulfate and distilled water is asfollows: first a measured quantity of chlorobutanol is dissolved in 500milliliters of distilled water with stirring and optionally using gentleheat to form a solution. Then, sodium chloride, oxime sulfate and L 3,4dipivalyla [(methylamino)methyl]benzyl alcohol bitartrate is added andthe solution stirred until clear. Next, distilled water is added to theliter mark and the ophthalmic solution filtered through a conventionalfilter having a 0.2 to 0.4 micron pore size. The solution will have ashelf-life stability of 3 years at 4 C. and its composition form is asfollows:

Ingredients: Per liter, gm. L 3,4 dipivalyl a [(methylamino)methyl]benzyl alcohol bitartrate 2.0 Sodium chloride 8.0 Chlorobutanol 5.0Oxime sulfate 0.1 Distilled water qs. 1 liter A second pharmaceuticalformulation similar to the formulation prepared immediately above ismade by following that procedure except that the amount of L-3,4-dipivalyl-a-[(methylamino)methyl]benzyl alcohol bitartrate is increasedto 10 grams and 2% phenylethyl alcohol is used as the preservative.

A novel lyophilized pharmaceutical preparation for subsequentreconstitution immediately before therapeutic administration is preparedas follows: first, 4 grams of L3,4-dipivalyl-a-[(methylamino)methyl]benzyl alcohol bitartrate and 8grams of mannitol U .S.P. are mixed With agitation into 1 liter ofdistilled water and the solution formed filtered through a sterilefilter. Then, cc. to 12 cc. of the solution is transferred to ambervials and lyophilized by conventional methods until the freshly formingcake is dry. The lyophilized, dry cake is reconstituted with cc. of adiluent containing the following: 2 grams sodium chloride, 5 grams ofchlorobutanol, 0.1 gram of oxime sulfate, mixed with distilled water tothe volume line in a 100 milliliter volumetric fiask.

The lyophilized cake can optionally be prepared by replacing themannitol with buffering agents such as a mixture of sodium chloride andsodium dihydrogen phosphate, or a mixture of potassium chloride andeither potassium acetate or sodium acetate.

Exemplary of formulations suitable for inhalation therapy include thoseformulations that can be administered from nebulizers of thesqueeze-bulb, reservoir. Venturi effect assembly, pressurized dispensersusing chlorofiuoro hydrocarbon propellants, pre micronized powders inliquid propellants, liquid-vapor phase aerosols, and the like.Typically, the formulation suitable for a conventional nebulizeroptionally is comprised of 0.4 to 0.8% solution of L 3,4dipivalyl-a-[(methylamino) methyl]benzyl alcohol hydrogen chloride in abuffered carrier comprised of sodium chloride, sodium citrate, glycerineand a trace of preservative. In one embodiment the air in the dispensercan be displaced with nitrogen gas. A typical pressurized dispenser canoptionally be 0.20 to 0.50% on a weight by weight basis ofL-3,4-dipivalyl-a- [(methylamino)methyl]benzyl alcohol in a mixture ofdichlorodifiuoromethane and dichlorotetrafluoroethane with a sodiumlactate lactic acid buffer, about to 40% weight by weight of an alkanoland aromatic flavoring agents. Other formulations containing thecompound of the invention suspended in fiuorochlorocarbons containingsorbitan trioleate and the like can also be used for administering thecompound.

The dose administered, whether a single dose or a daily dose, will, ofcourse, vary because of the chosen route of administration, and the sizeof the recipient. The dosage administered is not subject to definitebounds, but it will usually be an effective amount, or the equivalent ona molar basis of the pharmacologically active form pro duced upon themetabolic release of the active drug to achieve its desiredpharmacological and physiological effect. The medical dose for warmblooded mammals, including humans and primates by the intramuscular orsubcutaneous route will be about 100 micrograms to 5 milligramsadministered in 0.1 to 1.5 ml. of a 0.1 to 0.5 oil suspension, with theusual intramuscular dose of 200 to 750 micrograms in 0.2 to 0.75 ml. ofa 0.1 to 0.5% solution. For oral inhalation the dose is about 0.01 to2.0% applied as a fine mist. For typical application in operativeprocedures on the nose and throat, solutions of 0.002 to 0.975% may beused. Generally, the dosage form for a typical non-toxic salt, forexample, the bitartrate in an ophthalmic solution will be about 0.025 to4% and the like. The dose for farm animals is generally about 4 to 10ml. by the subcutaneous or intramuscular route for horses and cattle andfor dogs about 0.2 to 0.6 ml. and the like.

The unexpected, pronounced pharmacological properties for the compoundof the invention and its non-toxic salts are demonstrated by usingstandard art known testing procedures. For example, the mydriatic effectof the compound, which is useful for lowering intraocular pressureusually associated with antiglaucoma, is observed for the compound in agroup of rabbits by administering the active compound to their eyes andobserving the effects 20 minutes later. The test is carried out byapplying a 0.1% weight by volume isotonic saline solution L-3,4-dipivalyl-ed(methylamino)methyl]benzyl alcohol bitartrate to the eyes ofa mixed colony of New Zealand white rabbits and the eyes of the animalsobserved using the eyes of similar rabbits treated with non-acylated andother acylated compounds as a control. The observed results indicated nomydriasis for L-3,4-dihydroxy-a- [(methylamino)methyl]benzyl alcoholbitartrate, no mydriasis forL-3,4-diacetyl-u-[(methylamino)methyl]-benzyl alcohol hydroperchlorate,marginal mydriasis for L-3,4 dipropionyl-a-[(methylamino)methyl]benzylalcohol hydroperchlorate, marginal mydriasis for L-3,4-diisobutynyl-a-[(methylamino)methyl]benzyl alcohol hydroperchlorate, andextensive mydriasis for L-3,4-dipivalyl a-[(methylamino)methyl]benzylalcohol hydroperchlorate.

The anti-asthmatic effects of the compound of the invention isdemonstrated as follows: first, adult, male guinea pigs are exposed tothe nebulized spray of a 0.2% weight by volume spray ofL-3,4-dihydroxy-a-[(methylamino)methyl]benzyl alcohol equivalent insaline solution for 2 minutes in an inhalation chamber. With the controlanimals, only saline solution is nebulized. Next, the animals areexposed to a histamine challenge 10 minutes after exposure to thevarious tested compounds. The histamine challenge consists in exposingthe animals to the spray of a 0.2% weight by volume histaminediphosphate solution, and then recording the time before the onset ofthe first seizure. All the compounds were tested on an L-3,4dihydroxy-a-[(methylamino)methyl]benzyl alcohol basis, and the observedtimes are set forth in Table 1.

TABLE 1 Delay Before Onset Of Seizure in Minutes The enhanced stabilityof the compound is ascertained and compared against other compounds bymeasuring its rate of hydrolysis in a pH 4.5 acetate buffer solution atroom temperature and expressing the results as t days. The testsolutions had a concentration of 0.5 milligrams per milliliter, and therate of hydrolysis was measured in a spectrophatometer at 280 mg. Theresults are set forth in Table 2. Also in the same table is set forththe rate of auto-oxidation of a 0.2% olution at a pH of 4 in an airoxidative environment. These results are set forth as the time for colorformation, pink to brown, to develop in days from the first exposure ofthe solution to the environment.

The improved stability of the compound is demonstrated in variousbiological media by measuring its enzymatic rate of hydrolysis invarious media at 37 C. and expressing this result as the t life. Theenzymatic rate of hydrolysis is measured at pH of about 7.5 and at aconcentration of 0.5 mg./ml. of compound in media (a) horse serumcholinesterase, (b) rabbit serum, and (c) human plasma. The results forthe compound are listed in Table 3, as are the results of othercompounds treated in a like enzymatic environment. The free basecompound was measured by using high pressure liquid chromatography.

TABLE 3 Rate of hydrolysis in M2 seconds CompoundL-3,4-diacetyl-a-[(methy1amino)methyl]- Horse Rabbit Human The aboveexamples and disclosure are set forth merely for illustrating the modeand the manner of the invention. And, while various modifications andembodiments can be made by those skilled in the art, in the light ofthis invention, they are made without departing from the spirit of theinvention.

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically effectiveamount of a member selected from the group consisting of3,4-dipivalyl-a-[(methylamino)methyl]benzyl alcohol and itstherapeutically acceptable acid addition salts, admixed with apharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1 wherein thepharmaceutically effective amount consists of from 0.1 micrograms to 10grams of 3,4 dipivalyl-ot- [(methylamino)methyl]benzyl alcohol admixedwith a pharmaceutically acceptable carrier.

3. A pharmaceutical composition according to claim 1 wherein thecomposition consists of 0.01% to 2% of 3,4- dipivalyl a[(methylamino)methyl] benzyl alcohol and the carrier is atherapeutically acceptable inhalation carrier.

4. A pharmaceutical composition according to claim 1 wherein thecomposition consists of 0.25% to 4% of 3,4- dipivalyl a[(methylamino)methyl] benzyl alcohol and the carrier is atherapeutically acceptable opthalmic carrier.

5. A method for lowering intraocular pressure which method comprisesapplying topically to the eye an effective amount of compositioncomprising a topical opthalmic vehicle and 0.01 to 0.2% of a memberselected from the group consisting of 3,4 dipivalyl a [(methylamino)methyl]benzyl alcohol and a non-toxic acid addition salt thereof forlowering the intraocular pressure.

6. A method for relieving asthma in a warm blooded animal which methodcomprises administering an inhalation composition comprising aninhalation vehicle and 0.01 to 2% of a member selected from the groupconsisting of 3,4 dipivalyl a [(methylamino)methyl] benzyl alcohol, anda non-toxic acid addition salt thereof for relieving asthma.

References Cited Minatoya-Chem. Abst., vol. 74 (1971), p. 53268c.

SAM ROSEN, Primary Examiner

1. A PHARMACEUTICAL COMPOSITION COMPRISING A PHARMACEUTICALLY EFFECTIVEAMOUNT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF3,4-DIPIVALYL-A-(METHYLAMINO)METHYL)BENZYL ALCOHOL AND ITSTERAPEUTICALLY ACCEPTABLE ACID ADDITION SALTS, ADMIXED WITH APHARMACEUTICALLY ACCEPTABLE CARRIER.